The autoimmune disease Systemic Lupus Erythematosus (SLE) is characterized by a loss of tolerance to nu- clear antigens and the production of autoantibodies. These form immune complexes which promote inflammation and tissue damage. Several lines of evidence suggest that SLE pathogenesis is mediated by loss of adaptive immune tolerance coupled with hyperactivity of the innate immune system. The latter is associated with increased production of pro-inflammatory cytokines, including type I IFNs. Defining the molecular mechanisms that control these events may reveal novel therapeutic targets for SLE. We hypothesize that the transcription factor Foxo3 serves to attenuate the severity of lupus. Foxo3 is a member of the Foxo family of transcription factors which are downregulated by PI3 kinase signaling at both the mRNA and posttranslational levels. Our preliminary data indicate that Foxo3-deficient mice have altered immature B cell apoptosis and receptor editing, both means of central B cell tolerance. Foxo3 also has several unique anti-inflammatory roles in myeloid lineage cells. It dampens proinflammatory responses in dendritic cells and is known to limit the expression of type I IFNs and IFN signature genes in both human and murine macrophages. Elevated Foxo3 mRNA expression is associated with reduced severity of Crohn's disease and rheumatoid arthritis, and tumor- infiltrating dendritic cells are tolerogenic due to increased Foxo3 mRNA expression. This highlights the importance of Foxo3, and the control of its mRNA expression, in modulating inflammatory responses. Interestingly, preliminary analysis suggests that SLE patients fall into two distinct groups with respect to mRNA expression of Foxo3 and a cluster of associated genes (which we term the Foxo3 signature). Here, we will test the hypothesis that Foxo3 plays a protective role in lupus via the following Aims. In Aim 1, we will ask whether B cells that remain autoreactive after extensive BCR editing survive rather than undergo deletion in the absence of Foxo3. We will study editing and deletion in Foxo3-/- mice using a PCR assay of RS recombination, a measure of receptor editing, and an Ig Tg model in which autoreactive B cells are deleted. In Aim 2, we will determine whether mice that are prone to develop lupus have more severe disease in the absence of Foxo3, and if so which cell types mediate this effect. In Aim 3, we will compare SLE patients expressing low vs. high levels of Foxo3 for gene expression profiles and clinical disease parameters to determine whether patients with high levels of Foxo3 and associated signature genes have an altered disease course. This work will deter- mine whether Foxo3 limits the severity of lupus and characterize a unique set of Foxo3 associated biomarkers for a subset of SLE patients. These studies will also pave the way for new therapeutic approaches that target Foxo3 or Foxo3 signature genes.